title: Funneling and frustration in the energy landscapes of some designed and simplified proteins.
abstract: We explore the similarities and differences between the energy landscapes of proteins that have been selected by nature and those of some proteins designed by humans. Natural proteins have evolved to function as well as fold, and this is a source of energetic frustration. The sequence of Top7, on the other hand, was designed with architecture alone in mind using only native state stability as the optimization criterion. Its topology had not previously been observed in nature. Experimental studies show that the folding kinetics of Top7 is more complex than the kinetics of folding of otherwise comparable naturally occurring proteins. In this paper, we use structure prediction tools, frustration analysis, and free energy profiles to illustrate the folding landscapes of Top7 and two other proteins designed by Takada. We use both perfectly funneled (structure-based) and predictive (transferable) models to gain insight into the role of topological versus energetic frustration in these systems and show how they differ from those found for natural proteins. We also study how robust the folding of these designs would be to the simplification of the sequences using fewer amino acid types. Simplification using a five amino acid type code results in comparable quality of structure prediction to the full sequence in some cases, while the two-letter simplification scheme dramatically reduces the quality of structure prediction.
authors.affiliation: Department of Chemistry, Rice University, Houston, Texas 77005, USA.
authors.forename: Ha H
authors.initials: HH
authors.lastname: Truong
authors.forename: Bobby L
authors.initials: BL
authors.lastname: Kim
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Schafer
authors.forename: Peter G
authors.initials: PG
authors.lastname: Wolynes
mesh_terms: D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D011506:Proteins